Cell Cycle and Factors Involved in Inhibition or Progression of Breast Cancer [chapter]

Shazia Ali, Mohd Ishaq Dar, Rafiq A. Rather, Dil Afroze
2020 Breast Cancer Biology [Working Title]  
Cell cycle progression is driven by the sequential activation of a family of cyclindependent kinases (CDKs), which phosphorylate and activate proteins that execute events critical to cell cycle progression. Cell cycle checkpoints are scrutiny points that display the order, integrity, and fidelity of the major proceedings of the cell cycle. These comprise development to the correct cell size, the replication, integrity of the chromosomes, and their precise separation at mitosis. Many of these
more » ... hanisms are prehistoric in origin and highly preserved and hence have been deeply well versed by studies in model organisms such as the yeasts as well as in higher organisms. These molecular mechanisms switch alternative cell fates with substantial impact on tumor suppression. In the present study, we have explained different checkpoint pathways and the consequences of their dysfunction on cell fate in cancer. 2 cyclin E-Cdk2, cyclin A-Cdk2 during S phase, cyclin A-Cdk1, and cyclin B-Cdk1 during G2/mitotic phases. The control of the G2/M transition is important in all cancers resulting in chromosomal aberrations, but the G1/S transition involves many of the important cell-cycle events that may be altered in breast cancer. G1/S transition involves functions of the oncogenes/tumor suppressors cyclin E, cyclin D1, and p27 [5] . The oncogenic processes do occur by targeting the regulators of G1 phase progression [6] . During the G phase, cells respond to extracellular signals by either going into next division or withdraw from the cycle and thus are arrested in a state (Go). G1 progression is dependent on stimulation by mitogens or growth factors and can be blocked by anti-proliferative cytokines, but cancer cells do not obey these controls. Cancer cells remain in a continuous cycle of cell division by halting maturation and terminal differentiation. Once the cells pass a restriction point late in G1, they do not respond to extracellular growth regulatory signals and commit themselves to the independent program that causes cell division. The cells, which pass through the restriction point G1 and enter into S phase, which is controlled by cyclin-dependent protein kinases (CDKs) that are regulated by cyclins D, E, and A, are committed to divide. Cyclin D acts as growth factor regulator in response to extracellular signals in the cell cycle. The activity of Cyclin D depends on mitogenic stimulation upon binding with CDK4 and CDK6. Once bound, the catalytic activity of this complex is maximum in G1-S phase transition, but withdrawal of mitogen causes stoppage of cyclin D synthesis, and thus, the D cyclins holoenzyme activities decay rapidly, and the cells exit the cycle [7] . So, if cyclin DI-dependent kinase activity is lost before the restriction point, it prevents cells from entering S phase [8] . To pass through first check point -G1 phase that occurs in normal cell cycle, cyclin D-dependent kinases should phosphorylate protein retinoblastoma tumor suppressor protein (RB) [9] . As the hyper-phosphorylated RB gets dissociated from E2f, DP1, RB complex will result in the activation of E2F genes and leads to transcription of several genes such as cyclin E, cyclin A, and DNA polymerase. RB and other RB-like proteins (pI30, P107), which regulate gene expression which in turn are regulated by a family of heterodimeric transcriptional regulator E2Fs [10], which can transactivate genes and are required for S phase entry [11] . INK4 proteins inhibit (inhibitors of CDK4 and CDK6 INK4 proteins can directly block cyclin D-dependent kinase activity and cause G1 phase arrest) cyclin D-dependent kinases that phosphorylate RB. RB pathway does not functioning normal, which is feature of cancer cells [12] . The RB is inactivated by phosphorylation or by DNA damage; RB gene causes shrinking of G1 phase, and cell size is decreased. The mitogens and other signals required for cell are still present [13] . As the RB negative cells have few requirements for growth factors, these factors in addition to RB phosphorylation work for restriction point control [14] . As the cell cycle proceeds, the cyclin A-and cyclin B-dependent kinases keep RB in its hyperphosphorylated state. RB is not dephosphorylated until mitosis is completed and again renters the GI phase or Go. The activity of cyclin A synthesis occurs later in GI and is important for the G1-S transition, as blockage of cyclin A function in cells can also block S phase entry. For cell cycle progression, the inactivation of cyclin E and E2F is important when the cell enters S phase [15] . Cyclin B, B-cdc2 complex leads to stimulation of nuclear envelope and initiation of prophase, but its deactivation leads the cell to exit mitosis [16]. Drug resistance Hindrance in treating cancer patient mainly occurs by drug resistance [17] . Targeted therapies on breast cancer depend on the type of receptor being 3
doi:10.5772/intechopen.92576 fatcat:tqa2lj6hqjguvahzo3zcje2ose